The long-term goal of the proposed research program is to understand pathways through which the prefrontal cortex exercises central executive functions. Behavioral and physiologic studies in human and non-human primates suggest that the prefrontal cortex exercises inhibitory control on other areas, a process that is essential in attention, selection of relevant information, and suppression of irrelevant information in behavior. The goal of the proposed studies is to investigate the largely unexplored issue of prefrontal inhibitory control at the structural level in prefrontal-temporal pathways. The working hypothesis is that differences in inhibitory control in distinct prefrontal pathways are most parsimoniously explained by the diversity and regularity predicted by a conceptual model of patterns of cortical connections and their relationship to inhibitory neurons. This hypothesis is based on two key and consistent features based on quantitative data: (1) Corticocortical pathways have characteristic laminar origins and terminations that can be predicted by the structure of the linked areas. (2) The micro environment of connections varies significantly by region and layer in the density of distinct classes of inhibitory interneurons. This hypothesis will be tested by investigating the extent to which axons from prefrontal areas innervate inhibitory neurons in other prefrontal areas, and in temporal areas. The lateral and medial prefrontal areas under study are connected with each other and with temporal areas, and have a demonstrated role in inhibitory control in cognitive processes and motor control. Prefrontal pathways will be labeled with neural tracers, combined with double-labeling for parvalbumin or calbindin to label distinct classes of inhibitory neurons, and processed for correlated light and electron microscopic analysis. Information from this study will provide a foundation to understand the role of the prefrontal cortex in central executive functions, and the resulting imbalance in excitatory and inhibitory control in neurologic and psychiatric diseases affecting preferentially prefrontal-temporal pathways, including epilepsy and schizophrenia.